Human mesothelin is a 40 kDa cell-surface glycosylphosphatidylinositol (GPI)-linked glycoprotein. The protein is synthesized as a 69 kD precursor which is then proteolytically processed. The 30 kD amino terminus of mesothelin is secreted and is referred to as megakaryocyte potentiating factor (Yamaguchi et al., J. Biol. Chem. 269:805 808, 1994). The 40 kD carboxyl terminus remains bound to the membrane as mature mesothelin (Chang et al., Natl. Acad. Sci. USA 93:136 140, 1996).
Mesothelin is present at relatively low levels in mesothelial cells of the pleura, peritoneum and pericardium of healthy individuals, but is highly expressed in a number of different cancers, including mesotheliomas, stomach cancer, squamous cell carcinomas, prostate cancer, pancreatic cancer, lung cancer, and ovarian cancer (Hassan et al., Clin. Cancer Res. 10:3937-3942, 2004; McGuire et al., N. Engl. J. Med. 334:1-6, 1996; Argani et al., Clin. Cancer Res. 7:3862-3868, 2001; Hassan et al., Appl. Immunohistochem. Mol. Morphol. 13:243-247, 2005; Li et al., Mol. Cancer. Ther. 7:286-296, 2008; U.S. Pat. No. 7,081,518). In particular, it has been reported that a majority of serous carcinomas of the ovary and adenocarcinomas of the pancreas express high levels of mesothelin (Yen et al., Clin. Cancer Res. 12:827-831, 2006). In addition, high levels of mesothelin have been detected in greater than 55% of lung cancers and greater than 70% ovarian cancers (Hassan et al., Appl. Immunohistochem. Mol. Morphol. 13:243-247, 2005; Ho et al., Clin. Cancer Res. 13(5):1571-1575, 2007). The limited expression of mesothelin on normal cells makes it a viable target for tumor immunotherapy.
Mesothelin can also be used a marker for diagnosis and prognosis of certain types of cancer because trace amounts of mesothelin can be detected in the blood of some patients with mesothelin-positive cancers (Cristaudo et al., Clin. Cancer Res. 13:5076-5081, 2007). It has been reported that mesothelin may be released into serum through deletion at its carboxyl terminus or by proteolytic cleavage from its membrane bound form (Hassan et al., Clin. Cancer Res. 10:3937-3942, 2004). An increase in the soluble form of mesothelin was detectable several years before malignant mesotheliomas occurred among workers exposed to asbestos (Creaney and Robinson, Hematol. Oncol. Clin. North Am. 19:1025-1040, 2005). Furthermore, patients with ovarian, pancreatic, and lung cancers also have elevated soluble mesothelin in serum (Cristaudo et al., Clin. Cancer Res. 13:5076-5081, 2007; Hassan et al., Clin. Cancer Res. 12:447-453, 2006; Croso et al., Cancer Detect. Prev. 30:180-187, 2006).
Mesothelin-specific antibodies have potential as cancer therapeutic and diagnostic reagents. A major limitation in the clinical use of mouse monoclonal antibodies is the development of a human anti-murine antibody (HAMA) response. The HAMA response can involve allergic reactions and an increased rate of clearance of the administered antibody from the serum. A need remains for fully human antibodies that specifically bind mesothelin with high affinity, which can be used in the diagnosis and treatment of cancer. However, it is difficult to produce fully human antibodies to human antigens, as these antigens are generally recognized as self antigens.